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Drug-eluting sutures for Ophthalmic Surgery

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Optimized manufacture of drug-loaded sutures that meet size and strength requirements for ocular microsurgery and provide sustained delivery of a wide range of therapeutic and prophylactic drugs.

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Biomolecular Engineering
Chemical Engineering
Data Analytics
Drug-eluting sutures for Ophthalmic Surgery

Title:

Drug Eluting Device involving the use of ultra-thin, high strength, antibiotic-eluting sutures for prevention of ophthalmic infection (1), with an emphasis on improving the reproducibility of suture manufacturing and investigation of suture characteristics/attributes

Summary/Introduction:

The universal use of sutures at trauma sites and widespread applications in ophthalmic surgeries lend themselves to modulation. Modifications would allow for localized drug elution that would improve surgical and post-operative biological outcomes. By loading antibacterial or comparable drugs directly in medium, delivery can continue with sustained flow, and improve suture functionality (2). The method for preparation of these specialized devices relies on electrospun nanofibers into a single, ultra-thin, multifilament suture than meets both size and strength requirements for microsurgical ocular procedures. We aim to explore the efficacy of standardization in manufacturing procedures and post developmental traits such as tensile strength and binding properties/drug release rates. We are also pursuing scale manufacturing, while maintaining quality and efficacy standards of diameter and drug release requirements.

Main Proposal:

Objective:

Current commercially available and viable suture devices are associated with vision-threatening microbial keratitis and endophthalmitis, with complications implicated in up to 50% of infections following penetrating keratoplasty procedures (3,4,5,6,7,8). Sutures may grow weaker in strength, come loose or even break. Removal of such sutures after procedures such as cataract surgeries and Keratoprosthesis have shown bacterial contamination in almost 40% of cases (9). The goal of sustenance of drug delivery along with evaluations of ideas for improving strength is paramount, given the requirement to keep the device within the specifications of ‘medical-grade’. A drug/antibiotic-eluting suture allows reduction in suture-related postoperative infections and reductions in risk of infection following ocular device implantation. The platform used here allows for execution using a method of nanostructured filaments, through the novel electrospinning method. Such a method should be constructed to be sufficient and allow for the controlled release of a therapeutic moiety to improve surgical outcomes. Fabrication of such fibrous sutures involves the use of twisting drug loaded nanofibers that have been aligned through a variety of methods. The product results to be ultra-thin, multifilament sutures of specific diameters. These diameters are determined to be compliant and limited due to the inability of drug-loaded sutures to meet United States Pharmacopeia (U.S.P.) standards for suture strength (10,11). This program proposal aims to standardize and improve the procedures involved in the actual manufacturing and testing process of these sutures.

I will find a way to circumvent the shortcomings of the drug-coated suture, specifically relating to:

  • Meeting diameter requirements
  • Load sufficient quantities of drug, along with a variety of precursor compounds.
  • Control and monitoring both short-term and long-term drug release
  • Maintaining and improving scale manufacturing

The final bullet point is where most efforts will be focused. It is essential for the platform and manufacturing to be highly versatile and controlled. All sutures and their production must abide by strict procedures of reproducible manufacture, such that formulations, temperatures, and external factors are immune to the suture diameter. My work also categorically deals with the effects of humidity, electrospinning spray time and twist number. The procedures aim to be the only drug-loaded sutures that surpass U.S.P. breaking strength specifications (12,13,14,15).

Significance:

Local antibacterial functionality of such drug-eluting sutures allows for their application to be effective in cases of vulnerable surgical incision. They also provide postoperative alternatives for noncompliance with topical antibiotic eye drops. Other than this, these devices would be beneficial in settings of Glaucoma surgeries (trabeculectomy and use as drainage devices), Retinal detachment, vitrectomy, and Cataract surgery (12,13,14,15).

Using the procedure of improving scale manufacturing and controlling drug delivery, the sutures can be tested for all these settings. My study aims to improve the strength of such devices, when produced in uncontrolled/non-favorable conditions. By testing tensile strength, suture diameter and other USP meeting criteria at various humidity conditions, electrospinning duration and twist density, the study aims to find the efficacy of production in mass, and underdeveloped settings.

Methodology:

My study is a continuation of research that is ongoing with the postdoctoral fellows involved in the lab. The platform being utilized is changed across different combinations of unfavorable settings (high humidity, low electrospinning times etc.). The novel manufacturing system is capable of producing and twisting together hundreds of individual drug-loaded, polymeric nanofibers (Figure 1(a)). High voltages are applied to a polymer or polymer/drug solution pumped at a controlled flow rate to form polymeric fibers. While conditions are kept constant, certain characteristics are unchanged and required for USP clearance. At 1575 twists and 28 μm in diameter, multifilament PCL/8% Levo (levofloxacin) sutures surpass the minimum U.S.P. breaking strength specification for synthetic, absorbable, 10-0-sized sutures of 0.24 N. Levo, a fluoroquinolone and broad-spectrum ophthalmic antibiotic, is indicated for treatment of bacterial conjunctivitis. The biopolymer PCL is also used similarly as it is capable of long-term degradation and has a history of commercial usage as sutures (3,16,17,18,19) . With variations in spin time and twists, we find that rotation of one collector results in the twisting of deposited parallel fibers into a single 17-cm-long multifilament suture consistently. These fibers are then collected in parallel between two grounded collectors situated perpendicularly to the syringe pump. Following manufacture of sutures, along with manual twisting, drying and topical treatments, the sutures are prepared for usage by nylon-based binding. By utilizing an inbuilt system (maintains 25% humidity levels) as well as Dehumidifier (35% reduction of ambient humidity), humidity can be modulated and reduced such that twist density and count can be alleviated, without compromising on breaking strength. All productions from PCL must be comparable in both size and shape to commercially available 10-0 Ethilon® (nylon) sutures (Figure 1(b)). For the purposes of testing, rats are used for implantation with various nylon-suture based criteria, such as absence of postoperative care or topically administer Levo at single or multiple intervals. Bacterial colonization would be marked by highly enflamed and/or red eyes. My study will also involve the preparation of the rats along with observation and assistance of trained professionals to performed guided suture implantation. Animal study would only be conducted to humidity/condition modulated sutures that are part of groups that have undergone USP specified breaking strength testing, which will be part of my role in the lab. As part of my position at the lab, the process of maximizing fiber crystallinity, and consequently suture strength, by electrospinning nanofibers composed of a lower molecular weight PCL is paramount. Conditions must be modulated to improve polymer chain alignment and tensile strength (20) as well as maintaining USP specifications where artificial manipulation of conditions is impossible. Furthermore, variations in drugs (high hydrophobicity or lower degradation half-lives) can also be tested to help reduce the need for oral antibiotic use.

Timetable:

My position at the lab will be directly supervised by graduate student Aditya Josyula, with supervision and guidance from Dr. Kunal Parikh at the Center for Nanomedicine at the Wilmer Eye Institute and Center for Bioengineering Innovation & Design, under Dr. Laura Ensign’s laboratory. Dr. Parikh has experience with the intersection of nanomaterials, drug delivery and multi-faceted biomaterials, and will assist me with protocols, procedures, and testing/environment modulations. During the PURA period, I will be attending weekly lab-meetings and journal clubs held within Dr. Ensigns lab. Months 1-6 will be used for testing combinations of unfavorable conditions (uniformly increasing humidity levels, low electrospinning times, low twist density). Months 6-8 will be used for animal testing and burst antibiotic release studies. Months 8-10 will be used for assessing late-stage wound sealing. Months 10-12 will be for data analysis and abstract/manuscript preparation.

Results:

With my investigation being a part of ongoing lab research, the results are expected to be similar in terms of manufacturing process and general procedure. However, with alterations in experiment environments, controllable phenomenon and even compound usage, all devices are expected to be varied in characteristics such as tensile strength and twist diameter/density. Experiments will be repeated to allow for standardization of manufacturing practice, and allow for suture handling, reproducibility and efficacy in vitro and vivo testing.

Next Steps:

Using the results and testing from the studies, the aim is to standardize the manufacturing process and maximize reproducibility. We also aim to automate the method by the use of a unified platform in the future once all variables have been dealt with. By optimizing compounds and processes, utilization in unfavorable conditions (developing countries) will be possible. We plan to translate this technology platform for patient use in ophthalmology, where passive drug release is a necessity. These results will also be compiled as part of a separate finding. I hope to develop a manuscript and potentially attend undergraduate research conferences.

References:

  1. Parikh, KS, Omiadze, R, Josyula, A, et al. Ultra-thin, high strength, antibiotic-eluting sutures for prevention of ophthalmic infection. Bioeng Transl Med. 2021; 6:e10204. https://doi.org/10.1002/btm2.10204
  2. Lee D-H, Kwon T-Y, Kim K-H, et al. Anti-inflammatory drug releasing absorbable surgical sutures using poly(lactic-co-glycolic acid) particle carriers. Polym Bull. 2014;71(8):1933-1946.
  3. Ulery BD, Nair LS, Laurencin CT. Biomedical applications of biodegradable polymers. J Polym Sci B. 2011;49(12):832-864.
  4. Lee BJ, Smith SD, Jeng BH. Suture-related corneal infections after clear corneal cataract surgery. J Cataract Refract Surg. 2009; 35:939-942.
  5. Hood CT, Lee BJ, Jeng BH. Incidence, occurrence rate, and characteristics of suture-related corneal infections after penetrating keratoplasty. Cornea. 2011;30:624-628.
  6. Lin IH, Chang Y-S, Tseng S-H, Huang Y-H. A comparative, retrospective, observational study of the clinical and microbiological profiles of post-penetrating keratoplasty keratitis. Sci Rep. 2016;6:32751.
  7. Moorthy S, Graue E, Jhanji V, Constantinou M, Vajpayee RB. Microbial keratitis after penetrating keratoplasty: impact of sutures. Am J Ophthalmol. 2011;152(2):189-194.e182.
  8. Christo CG, van Rooij J, Geerards AJM, Remeijer L, Beekhuis WH. Suture-related complications following keratoplasty: a 5-year retrospective study. Cornea. 2001;20(8):816-819.
  9. Heaven CJ, Davison CR, Cockcroft PM. Bacterial contamination of nylon corneal sutures. Eye (Lond). 1995;9(Pt 1):116-118.
  10. Pruitt LA, Chakravartula AM. Mechanics of biomaterials: fundamental principles for implant design. MRS Bull. 2012;37(7):698.
  11. Kashiwabuchi F, Parikh KS, Omiadze R, et al. Development of absorbable, antibiotic-eluting sutures for ophthalmic surgery. Transl Vis Sci Technol. 2017;6(1):1-1.
  12. Hu W, Huang ZM, Liu XY. Development of braided drug-loaded nanofiber sutures. Nanotechnology. 2010;21(31):315104.
  13. Padmakumar S, Joseph J, Neppalli MH, et al. Electrospun polymeric core–sheath yarns as drug eluting surgical sutures. ACS Appl Mater Interfaces. 2016;8(11):6925-6934.
  14. Weldon CB, Tsui JH, Shankarappa SA, et al. Electrospun drug-eluting sutures for local anesthesia. J Control Release. 2012;161(3):903-909.
  15. He C-L, Huang Z-M, Han X-J. Fabrication of drug-loaded electrospun aligned fibrous threads for suture applications. J Biomed Mater Res A. 2008;89A:80-95.
  16. Healy DP, Holland EJ, Nordlund ML, et al. Concentrations of levofloxacin, ofloxacin, and ciprofloxacin in human corneal stromal tissue and aqueous humor after topical administration. Cornea. 2004;23(3):255-263.
  17. Dash TK, Konkimalla VB. Poly-є-caprolactone based formulations for drug delivery and tissue engineering: a review. J Control Release. 2012;158(1):15-33.
  18. Woodruff MA, Hutmacher DW. The return of a forgotten polymer—polycaprolactone in the 21st century. Prog Polym Sci. 2010;35(10):1217-1256.
  19. Dash TK, Konkimalla VB. Polymeric modification and its implication in drug delivery: poly-εcaprolactone (PCL) as a model polymer. Mol Pharm. 2012;9(9):2365-2379.
  20. Zhang S, Liu X, Barreto-Ortiz SF, et al. Creating polymer hydrogel microfibres with internal alignment via electrical and mechanical stretching. Biomaterials. 2014;35(10):3243-3251.